18-3534226-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004746.4(DLGAP1):c.2447G>A(p.Arg816Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0224 in 1,614,058 control chromosomes in the GnomAD database, including 482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R816W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (34 hom., cov: 32)
  • Exomes 𝑓: 0.023 (448 hom.)
• Consequence: DLGAP1 NM_004746.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.87

Genes affected

DLGAP1 (HGNC:2905): (DLG associated protein 1) Predicted to enable molecular adaptor activity. Predicted to be a structural constituent of postsynaptic density. Predicted to be involved in several processes, including aggresome assembly; regulation of postsynaptic neurotransmitter receptor activity; and regulation of proteasomal protein catabolic process. Predicted to be located in plasma membrane. Predicted to be part of postsynaptic density. Predicted to be active in glutamatergic synapse and postsynaptic density, intracellular component. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004804611).
• BP6: Variant 18-3534226-C-T is Benign according to our data. Variant chr18-3534226-C-T is described in ClinVar as [Benign]. Clinvar id is 3037438.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0164 (2493/152292) while in subpopulation NFE AF= 0.0283 (1927/68026). AF 95% confidence interval is 0.0273. There are 34 homozygotes in gnomad4. There are 1112 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2494 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLGAP1	NM_004746.4	c.2447G>A	p.Arg816Gln	missense_variant	10/13	ENST00000315677.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLGAP1	ENST00000315677.8	c.2447G>A	p.Arg816Gln	missense_variant	10/13	5	NM_004746.4	P1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2494 AN: 152174 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.0155 AC: 3898 AN: 250866 Hom.: 50 AF XY: 0.0155 AC XY: 2102 AN XY: 135562

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00752

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00392

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0264

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0230 AC: 33659 AN: 1461766 Hom.: 448 Cov.: 33 AF XY: 0.0225 AC XY: 16326 AN XY: 727178

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.00816

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00404

Gnomad4 FIN exome AF: 0.0152

Gnomad4 NFE exome AF: 0.0275

Gnomad4 OTH exome AF: 0.0182

GnomAD4 genome AF: 0.0164 AC: 2493 AN: 152292 Hom.: 34 Cov.: 32 AF XY: 0.0149 AC XY: 1112 AN XY: 74464

Gnomad4 AFR AF: 0.00503

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.0283

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0237 Hom.: 79

Bravo AF: 0.0157

TwinsUK AF: 0.0278 AC: 103

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0255 AC: 219

ExAC AF: 0.0160 AC: 1942

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0228

EpiControl AF: 0.0234

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DLGAP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	-0.063
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D;.;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0048	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.69	N;N;N;N;.;N;N;N;.;N;.
REVEL	Benign	0.068
Sift	Benign	0.28	T;T;T;T;.;T;T;T;.;T;.
Sift4G	Benign	0.59	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.014	B;.;.;.;.;B;.;.;.;B;.
Vest4		0.16
MPC		1.0
ClinPred		0.014	T
GERP RS		5.9
Varity_R		0.095
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35822832; hg19: chr18-3534224;